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J. Biol. Chem., Vol. 280, Issue 37, 32379-32388, September 16, 2005

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T-oligo Treatment Decreases Constitutive and UVB-induced COX-2 Levels through p53- and NFB-dependent Repression of the COX-2 Promoter^*

Vaneeta Marwaha1, Ya-Hui Chen12, Elizabeth Helms, Simin Arad, Hiroyasu Inoue, Evelyn Bord¶, Raj Kishore¶, Raffi Der Sarkissian||, Barbara A. Gilchrest3, and David A. Goukassian4

From the Departments of Dermatology and ^||Division of Facial Plastic and Reconstructive Surgery, Boston University School of Medicine, Boston, Massachusetts 02118, Nara Women's University, Nara 630-8506, Japan and ^¶Division of Cardiovascular Research, St. Elizabeth's Medical Center, Boston, Massachusetts 02135

Chronically irradiated murine skin and UV light-induced squamous cell carcinomas overexpress the inducible isoform of cyclooxygenase (COX-2), and COX-2 inhibition reduces photocarcinogenesis in mice. We have reported previously that DNA oligonucleotides substantially homologous to the telomere 3'-overhang (T-oligos) induce DNA repair capacity and multiple other cancer prevention responses, in part through up-regulation and activation of p53. To determine whether T-oligos affect COX-2 expression, human newborn keratinocytes and fibroblasts were pretreated with T-oligos or diluent alone for 24 h, UV-irradiated, and processed for Western blotting. In both cell types, T-oligos transcriptionally down-regulated base-line and UV light-induced COX-2 expression, coincident with p53 activation. In fibroblasts with wild type versus dominant negative p53 (p53^WT versus p53^DN), T-oligos decreased constitutive expression of a COX-2 reporter plasmid by >50%. We then examined NFB, a known positive regulator of COX-2 transcription. In p53^WT but not in p53^DN fibroblasts and in human keratinocytes, T-oligos decreased readout of an NFB promoter-driven reporter plasmid and decreased NFB binding to DNA. After T-oligo treatment and subsequent UV irradiation, binding of the transcriptional co-activator protein p300 to NFB was decreased, whereas binding of p300 to p53 was increased. Human skin explants provided with T-oligos had markedly decreased COX-2 immunostaining both at base-line and post-UV light, coincident with increased p53 immunostaining. We conclude that T-oligos transcriptionally down-regulate COX-2 expression in human skin via activation and up-regulation of p53, at least in part by inhibiting NFB transcriptional activation. Decreased COX-2 expression may contribute to the observed ability of T-oligos to reduce photocarcinogenesis.

Received for publication, March 24, 2005 , and in revised form, July 14, 2005.

^* This work was supported in part by National Institutes of Health Grant RO-1 CA105156-01 and by the Herzog Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. S1–S7.

¹ Both authors contributed equally to this work.

² Supported by the Veterans General Hospital, Kaohsiung, Taiwan. Present address: Dept. of Dermatology, Veterans General Hospital, Kaohsiung, Taiwan.

³ To whom correspondence may be addressed: Dept. of Dermatology, Boston University School of Medicine, 609 Albany St., Boston, MA 02118. Tel.: 617-638-5541; Fax: 617-638-5515; E-mail: bgilchre{at}bu.edu. ⁴ To whom correspondence may be addressed: Dept. of Dermatology, Boston University School of Medicine, 609 Albany St., Boston, MA 02118, Tel.: 617-638-5541; Fax: 617-638-5515; E-mail: dgoukass{at}bu.edu.

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